JP6670310B2 - Preparation of synthetic intermediates for the preparation of tetrahydroquinoline derivatives - Google Patents

Description

  INDUSTRIAL APPLICABILITY The present invention has an inhibitory activity on cholesteryl transfer protein (CETP), has the effect of increasing HDL cholesterol level and decreasing LDL cholesterol level, The present invention relates to a method for preparing a synthetic intermediate which can be used for preparing a tetrahydroquinoline derivative which can be used for treating and / or preventing a disease of the present invention.

  Promising epidemiological studies have shown a strong association between low density lipoprotein cholesterol (LDL-C) levels and cardiovascular disease (CVD) risk [1]. Applying subsequent statin therapy to reduce these atherosclerotic LDL-C levels significantly reduces CVD-related morbidity and mortality. That is, it is estimated that each 1 mmol / L decrease in LDL-C reduces CVD events by 22% and all-cause mortality by 10% [2]. Despite these excellent benefits, there remains a significant burden of disease that has a significant impact on both individual patients and broad medical costs [3]. New therapies are needed to further reduce this risk of residual CVD in patients.

  One new approach to reducing LDL-C and increasing high density lipoprotein cholesterol (HDL-C) levels is to inhibit cholesterol transesterification protein (CETP). CETP is a plasma protein secreted primarily by liver and adipose tissue. CETP mediates the transfer of cholesteryl ester from HDL to apolipoprotein B (Apo B) -containing particles (mainly LDL and very low density lipoprotein VLDL) in exchange for triglycerides, thereby (V) LDL conversion. The cholesterol content in HDL has been reduced to favor the content. Therefore, inhibition of CETP has been postulated to retain cholesteryl esters in HDL-C and reduce the cholesterol content of the atherosclerotic Apo B fraction.

  Despite evidence supporting the potential of CETP inhibition in reducing the prevalence of cardiovascular disease, clinical development of CETP inhibitors is not easy. The first compound to progress to phase III clinical trials is torcetrapib, which has shown efficacy but has a greater safety profile when combined with atorvastatin, such as unexpected cardiovascular events and death compared to atorvastatin alone It was not developed due to concerns about gender [4].

  Another CETP inhibitor, darcetrapib, which entered phase IIb clinical trials increased HDL-C by 30-40% with minimal effect on LDL-C concentration, while the off-target effect of torcetrapib Were shown to be weak inhibitors [11-13]. In recent years, dalcetrapib development has also been terminated due to the futility of a Phase III study conducted with this compound.

  Two additional CETP inhibitors, anacetrapib and evasetrapib, are currently in phase III clinical trials. However, the use of these CETP inhibitors has the disadvantage that relatively high doses must be used to obtain CETP inhibition, and more severe side effects can occur. This can have an adverse effect on both the patient's physical health and patient compliance.

  The present inventors have successfully overcome the aforementioned disadvantages by providing potent and well-tolerated CETP-inhibitors and pharmaceutical compositions thereof. This CETP-inhibitor is a tetrahydroquinoline derivative referred to as Compound A and has the following structural formula:

を有する。

Having.

  Clinical trials have shown that Compound A (or a salt thereof) is a potent and potent CETP-inhibitor. Compared to other known CETP-inhibitors, Compound A requires relatively small doses to reach almost complete CETP inhibition. Typically, repeated administration of Compound A once daily at a low dose of 2.5 mg has already been demonstrated to be sufficient to reach almost complete CETP inhibition. These are significantly lower doses than those to be used for other CETP-inhibitors. In addition, clinical trials have also shown that Compound A is well tolerated and does not cause serious side effects.

  In the preparation of tetrahydroquinoline derivatives such as compound A, the compounds of formula I:

に従う中間体が使用されている。

The intermediates according to are used.

  While these types of intermediates are very useful for the preparation of tetrahydroquinoline derivatives such as Compound A, using current methods of preparing these types of intermediates as described in WO2007 / 116922, The overall yield will be relatively low. In addition, relatively expensive starting materials and catalysts, such as (R) -3-aminovaleric acid and palladium, respectively, must be used. Further, the current preparation method has a problem of corrosion of the production tool due to residual fluorine.

  Accordingly, there is a need for an efficient and cost-effective method for preparing intermediates according to Formula I that can be used to further prepare tetrahydroquinoline derivatives having CETP inhibiting properties, such as Compound A. I have.

  A first aspect of the present invention is a compound of formula I:

の化合物またはその塩の調製方法であって、
（ａ）式ＩＩ：

A method for preparing a compound or a salt thereof,
(A) Formula II:

に従う４−アミノベンゾトリフルオリドと、
式ＩＩＩ：

4-aminobenzotrifluoride according to
Formula III:

に従うアルデヒド、及び式ＩＶ：

And an aldehyde according to formula IV:

に従う化合物とを、溶剤及び任意に１種以上の触媒の存在下で反応させて、式Ｖ：

With a compound according to formula V in the presence of a solvent and optionally one or more catalysts,

に従う化合物
（式中、Ｒ_１はＨまたはＣ_１−Ｃ_３アルキル、好ましくはＣＨ_２ＣＨ_３であり、
Ｒ_２はＨ、Ｃ_１−Ｃ_３アルキルまたは

Wherein R ₁ is H or C ₁ -C ₃ alkyl, preferably CH ₂ CH ₃ ,
R ₂ is H, C ₁ -C ₃ alkyl or

である。）を形成する工程と、
（ｂ）式Ｖの化合物を加水分解して式Ｉの化合物を形成する工程と、を含む、方法に関する。

It is. ), And
(B) hydrolyzing the compound of Formula V to form a compound of Formula I.

  By using the process of the present invention, it is now possible to efficiently prepare intermediate compounds according to formula I with relatively inexpensive starting materials, little formation of by-products and in good yields . As mentioned above, these compounds can be used for further preparation of tetrahydroquinoline derivatives such as compound A.

  In the process according to the invention, a so-called three-component Povarov reaction is used. An important step in this method is that of formula V:

に従ういわゆるポヴァロフ生成物の形成である。この中間体は比較的安価な出発材料を用いて調製することができ、かつ効率的に加水分解して式Ｉに従う化合物を形成することができる。

Is the formation of the so-called Povarov product. This intermediate can be prepared using relatively inexpensive starting materials and can be efficiently hydrolyzed to form compounds according to Formula I.

  Accordingly, a second aspect of the present invention relates to an intermediate according to formula V. This intermediate has never been prepared before.

  A third aspect of the invention relates to the use of an intermediate according to formula V in the preparation of a compound according to formula I, in particular the preparation of a 2R, 4S enantiomer according to formula Ia. The enantiomer can be used for the preparation of compound A.

  Accordingly, a last aspect of the invention relates to the use of a compound according to formula V in the preparation of compound A.

Definitions As used herein, the term "pharmaceutically acceptable" has its conventional meaning, without undue toxicity, inflammation, allergic reactions, and any other corresponding to a reasonable benefit / risk ratio. The compounds, materials, compositions and / or dosage forms within the scope of sound medical judgment suitable for contact with mammalian, especially human tissue, without complicating the problem of

  The term “salt” as used herein has its conventional meaning and includes acid adducts and base salts.

  The term "treatment" as used herein has its conventional meaning and refers to therapeutic, palliative, and prophylactic treatment.

  The term “cardiovascular disease” has its conventional meaning, arteriosclerosis, peripheral vascular disease, hyperlipidemia, mixed dyslipidemia β lipoproteinemia, hypoalpha lipoproteinemia, hypercholesterolemia Hypertriglyceridemia, familial hypercholesterolemia, angina, local anemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction and stroke including.

  The terms “halo”, “halogen atom” or “halogen” refer to fluorine, chlorine, bromine or iodine.

  As used herein, the term "alkyl" or "alkyl group" has its conventional meaning and refers to a straight or branched saturated hydrocarbon chain having 1 to 10 carbon atoms and 3 to 10 carbon atoms. Refers to a cyclic saturated hydrocarbon chain having the following carbon atoms:

The term “C ₁ -C ₃ alkyl” as used herein has its conventional meaning and refers to an alkyl group having 1 to 3 carbon atoms. Examples of such alkyl groups include methyl, ethyl, propyl and isopropyl.

  Methods for preparing tetrahydroquinoline derivatives are described in WO2007 / 116922. Tetrahydroquinoline derivatives, such as compound A, can be prepared by the methods described above, but with low yields and producing high levels of unwanted by-products. In addition, expensive starting materials such as (R) -3-aminovaleric acid were used in this method. It has been found that the preparation of compounds according to formula I (such as DIAM in the above method) is particularly cumbersome and expensive.

  To solve these problems, an improved method for preparing compounds according to formula I has been developed by the present inventors. Surprisingly, it has been found that compounds according to formula I can be prepared using a so-called three-component Povarov reaction.

  The Povarov reaction is a ternary reaction in which cis-2-alkyl-4-amino-1,2,3,4-tetrahydroquinone is formed in one stereoselective step of aniline, aldehyde, and enamine (Tetrahedron 2009). , 65, 2721). The use of this reaction has been reported in this document, but its application in preparing pharmaceutically active ingredients has been limited due to concerns regarding storage stability and product purity.

Therefore, the first aspect of the present invention is:
Formula I:

の化合物またはその塩の調製する方法であって、
（ａ）式ＩＩ：

A method for preparing a compound or a salt thereof, comprising:
(A) Formula II:

に従う４−アミノベンゾトリフルオリドと、
式ＩＩＩ：

4-aminobenzotrifluoride according to
Formula III:

に従うアルデヒド及び、式ＩＶ：

And an aldehyde according to formula IV:

に従う化合物とを、溶剤及び任意に１種以上の触媒の存在下に反応させて、式Ｖ：

With a compound according to formula V in the presence of a solvent and optionally one or more catalysts,

に従う化合物（式中、Ｒ_１は、ＨまたはＣ_１−Ｃ_３アルキル、好ましくはＣＨ_２ＣＨ_３であり、
Ｒ_２は、Ｈ、Ｃ_１−Ｃ_３アルキルまたは

Wherein R ₁ is H or C ₁ -C ₃ alkyl, preferably CH ₂ CH ₃ ,
R ₂ is H, C ₁ -C ₃ alkyl or

である。）を形成する工程と、
（ｂ）式Ｖの化合物を加水分解して式Ｉの化合物を形成する工程と、を含む、方法に関する。

It is. ), And
(B) hydrolyzing the compound of Formula V to form a compound of Formula I.

  Using the process of the present invention, it is now possible to efficiently prepare compounds of formula I with relatively inexpensive starting materials, without the production of many unwanted by-products, and in good yields. is there.

In the preparation of compound A, the use of a compound of the invention (wherein R ₁ is CH ₂ CH ₃ and R ₂ is H) in the process is preferred. In such a case, the aldehyde according to formula III is propionaldehyde and the compound according to formula IV is N-vinylformamide.

  After steps a) and b) of the process according to the invention have been carried out, an important intermediate according to formula I is obtained, which can be used for the further preparation of tetrahydroquinoline derivatives such as compound A.

  Because compounds according to Formula I are chiral, it is desirable to at least partially separate or purify the different enantiomers of the compound of Formula I. Such separations or purifications are well-known in the art, and those skilled in the art can easily utilize a plurality of methods to perform such separations or purifications.

  One preferred method of at least partially separating or purifying the different enantiomers is the use of a chiral resolving agent such as L-tartaric acid, or a derivative thereof (such as di-p-toluoyl-L-tartaric acid).

  The preparation of tetrahydroquinoline derivatives having CETP inhibitory properties (eg compound A) most often requires the use of the 2R, 4S enantiomer of the compound according to formula I. Thus, in a further step c) of the process of the invention, in formula Ia:

に従う２Ｒ，４Ｓエナンチオマーが他の立体異性体から分離されることが好ましい。

It is preferred that the 2R, 4S enantiomer according to is separated from other stereoisomers.

  With respect to the preparation of compound A, compound B ((2R, 4S) -2-ethyl-6-trifluoroethyl-1,2,3,4-tetrahydroquinolin-4-ylamine in WO2007 / 116922) Called) :.

を分離することが好ましい。

Is preferably separated.

  Separation or purification of the compound according to formula I results in a compound according to formula Ia or compound B having at least 99% enantiomeric excess (ee), preferably at least 99.6% enantiomeric excess, More preferably, it is preferably obtained with an enantiomeric excess of at least 99.7%.

  After obtaining these compounds, they can be reacted by using methods similar to those described in WO2007 / 116922 to give tetrahydroquinoline derivatives having CETP inhibitory properties (eg compound A).

  In one preferred embodiment of the invention, the stoichiometry of the reaction between the aldehyde having formula III, the amide compound having formula IV and the 4-aminobenzotrifluoride having formula II is 0.5-5 (:) 1 (:) is in the range of 0.5 to 1.

The yield of compounds according to formula I may also depend on the solvent used in step a). Preferably, the solvent used is dichloromethane, acetonitrile, ethyl acetate, toluene, or a mixture thereof. When R ₁ is CH ₂ CH ₃ and R ₂ is H, the reaction of step a) is preferably carried out in dichloromethane, acetonitrile or a mixture of toluene and dichloromethane.

  In a preferred embodiment of the invention, the catalyst used in step a) of the invention is an acid, preferably a Bronsted acid, or a Lewis acid.

  In a further preferred embodiment of the invention, the reaction between the aldehyde having the formula III and the amide compound having the formula IV and 4-aminobenzotrifluoride having the formula II is carried out in the presence of an acid-catalyzed 4-toluenesulfonic acid. Done in There are many modes of addition that can successfully provide the desired product. A simultaneous addition mode is preferred, which can prevent the formation of product-related impurities that are difficult to remove.

  In step a) of the process according to the invention, preference is given to adding the mixture of 4-aminobenzotrifluoride according to formula II and the catalyst to the aldehyde according to formula III simultaneously with the addition of the compound according to formula IV.

  Alternatively, the aldehyde according to formula III, the compound according to formula IV, and the 4-aminobenzotrifluoride according to formula II are first mixed in a solvent according to the invention, after which the compound is contacted with the catalyst.

  Alternatively, the aldehyde according to formula III and the 4-aminobenzotrifluoride according to formula II are first mixed in a solvent according to the invention, after which they are contacted with a compound according to formula IV and a catalyst according to the invention.

  In order to further improve the yield and purity of the compounds according to formula I, the present inventors have separated the compounds of formula V formed in step a) (ie the Povarov product) from the reaction mixture, It has been found that performing b) is beneficial.

  Preferably, the compound of formula V is separated by a precipitation and / or filtration procedure before step b). Precipitation of the compound of formula V from the reaction product can be performed by adding a non-polar solvent to the reaction mixture. Preferably, the non-polar solvent is heptane, cyclohexane, or a mixture thereof.

  If necessary, purification is carried out with the compound of the formula V by a two-stage precipitation method. To this end, the compound having formula V is precipitated in a first stage with heptane or cyclohexane, or a mixture thereof, and then recrystallized in a second precipitation stage with acetone, isopropanol, ethyl acetate or methyl tert-butyl ether. Preferably. Further, precipitation and / or recrystallization can be performed to further increase the purity of the compound having Formula V.

  In step b) of the process of the invention, the compound having formula V is hydrolyzed to form a compound of formula I. Such hydrolysis is preferably carried out by warming the mixture containing the compound of formula V in the presence of a water-soluble acid, preferably hydrochloric acid, at a temperature of 45 to 80 ° C for 1 to 3 hours.

  In a preferred embodiment of the process according to the invention, the compound according to formula V is hydrolyzed in the presence of an alcohol, preferably ethanol, and a water-soluble acid.

  Compounds according to formula Ia, in particular compound B, may be further used for the preparation of tetrahydroquinoline derivatives having CETP inhibitory properties (for example compound A) by using a method similar to that described in WO2007 / 116922. Is preferred.

  A second aspect of the present invention provides a compound of formula V:

（式中、Ｒ_２は、Ｈ、Ｃ_１−Ｃ_３アルキル、または

Wherein R ₂ is H, C ₁ -C ₃ alkyl, or

である。）
に従う化合物に関する。

It is. )
According to the invention.

The compound of formula V is a so-called Povalov compound and has never been synthesized before. Compounds according to Formula V, wherein R ₁ is CH ₂ CH ₃ and R ₂ is H, are particularly preferred because they are extremely efficient for use in preparing Compound A.

  A third aspect of the invention relates to the use of these compounds in the preparation of compounds according to formula Ia, in particular in the preparation of compound B.

  A last aspect of the invention relates to the use of a compound of formula V in the preparation of compound A.

  The present invention is further described by, but not limited to, the following non-limiting examples.

Example 1: Preparation of racemic cis-N- (2-ethyl-6- (trifluoromethyl) -1,2,3,4-tetrahydroquinolin-4-yl) formamide (Povarov product)

実施例１ａ）同時添加を用いた、３ｍｏｌ％のトルエンスルホン酸（ＴｓＯＨ）触媒三成分ポヴァロフ反応（５０ｇスケール）
反応器Ａに、プロピオンアルデヒド（９０ｇ、５当量（ｅｑ））及びアセトニトリル（５０ｍｌ）を添加し、反応器Ｂにｐ−トルエンスルホン酸（１．７７ｇ、３ｍｏｌ％）、４−トリフルオロメチルアニリン（５０ｇ、１当量）及びアセトニトリル（１００ｍＬ）を添加し、反応器Ｃに、Ｎ−ビニルホルムアミド（２６．５ｇ、１．２当量）及びアセトニトリル（１００ｍＬ、２容量（ｖｏｌｓ））を添加した。

Example 1a) 3 mol% toluene sulfonic acid (TsOH) catalyzed ternary Povalov reaction using simultaneous addition (50 g scale)
To the reactor A, propionaldehyde (90 g, 5 equivalents (eq)) and acetonitrile (50 ml) were added, and to the reactor B, p-toluenesulfonic acid (1.77 g, 3 mol%), 4-trifluoromethylaniline ( 50 g, 1 eq) and acetonitrile (100 mL) were added and to reactor C was added N-vinylformamide (26.5 g, 1.2 eq) and acetonitrile (100 mL, 2 vols).

  The contents of Reactor B and Reactor C were simultaneously added to Reactor A over a period of about 4 hours, while maintaining the temperature of the contents of Reactor A at 20-30 ° C. After the addition, the reaction mixture in reactor A was stirred at 20-25 <0> C for 16 hours. Thereafter, the mixture was cooled to 0-5 ° C and stirred for 3 hours. The precipitate was filtered and washed with cold acetonitrile (100 mL). Thereafter, the solid was dried under vacuum at 40 ° C. for 16 hours to obtain 31 g of Povarov product (37% yield).

Example 1b) 2 mol% toluenesulfonic acid (TsOH) catalyzed ternary Povalov reaction (100 g scale) in dichloromethane overnight
4-amino-benzotrifluoride are dissolved (100g, 78mL, 0.62mol) in _CH 2 _Cl 2 (200mL) at room temperature. Propionaldehyde (44.7mL, 0.62mol), followed by the addition of _CH 2 _Cl 2 (200mL). The clear solution was stirred at room temperature for 1 hour to give a light yellow solution of the imine. The reaction mixture was further diluted with _CH 2 _Cl 2 (300mL), and cooled on ice. N-vinylformamide (86.8 mL, 1.24 mol, 2.0 equiv) was added in one portion to the in situ prepared imine solution as described above. TsOH (2.36 g, 12.4 mmol, 2 mol%) was added to the reaction mixture, and the reaction mixture was stirred on ice at 0 ° C. to room temperature overnight. Heptane (700 mL) was added to the suspension. After 5 minutes, the slurry was suction filtered through a glass filter. Off-white crystals were suction washed on the filter with heptane (2 × 200 mL). The obtained solid was dried at 50 ° C. under reduced pressure using a rotary evaporator to obtain a product (99 g, yield 59%) as an off-white solid. The product was confirmed by liquid chromatography-mass spectrometry (LCMS) and ¹ H-nuclear magnetic resonance (NMR). Next, the crude solid was recrystallized from hot acetone. Undissolved solids were removed from the hot acetone solution by filtration. The resulting clear solution was stored at 5 ° C. overnight. The resulting thick slush was filtered through a glass filter and washed with heptane (2 × 200 mL). This resulted in 52.5 g of a white solid (32% yield). The mother liquor was evaporated and recrystallized from isopropanol (IPA) (± 100 mL) to give 13.5 g of a white solid. Both batches were combined to give a yield of 66 g (39% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.40 (s, 1 H), 7.34 (t, 1 H), 7.26 (d, J = 7.7 Hz, 1 H), 6.52 (D, J = 8.4 Hz, 1H), 5.88-5.54 (m, J = 26.6 Hz, 1H), 5.52-5.36 (m, 1H), 4.85 -4.67 (m, J = 16.3, 10.8 Hz, 1H), 4.14 (s, 1H), 3.58-3.31 (m, 1H), 2.45- 2.30 (m, 1H), 1.80-1.36 (m, 4H), 1.03 (t, 3H).

Example 2 Preparation of Compound B Example 2a) Racemic 2-ethyl-6- (trifluoromethyl) -1,2,3,4-tetrahydroquinolin-4-amine (racemic-Compound B)
A mixture of the Povarov product (20 g, 73.5 mmol), concentrated HCl (22.3 mL), and ethanol (60 mL) was heated at 50 ° C. for 5 hours. After cooling to 30-40 ° C., the mixture was evaporated to a total volume of 60 mL. Thereafter, the mixture was cooled, dichloromethane (160 mL) was added, and then basified with 6 M NaOH (60 mL) to pH 12-13. The layers were separated and the liquid phase was extracted with dichloromethane (40mL). The combined organic layers were washed with water (40 mL), dried over sodium sulfate and evaporated to dryness to give 17.6 g of racemic compound B (95% yield).

Example 2b) Racemic 2-ethyl-6- (trifluoromethyl) -1,2,3,4-tetrahydroquinolin-4-amine (racemic compound B) (in acetonitrile followed by sulfuric acid hydrolysis)
It was dissolved at room temperature (RT) with 4-amino-benzotrifluoride (6.3 mL, 50.0 mmol) and _CH 3 CN (40mL). Propionaldehyde (4.3 mL, 60 mmol, 1.2 eq, stored at 4 ° C.) was added in one portion. The temperature was raised to 25C. The clear solution was stirred at room temperature (in a water bath for cooling) for 5 minutes to give a pale yellow solution of the imine. N-vinylformamide (4.4 mL, 63 mmol, 1.25 eq, stored at 4 ° C.) was added in one portion to the in situ prepared imine solution, followed by TsOH (160 mg, 0.017 eq). The temperature was raised to 27C. After 5 minutes, a precipitate had formed. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. NMR analysis indicated that the components had been completely converted to the Povarov product. Water (140 mL) was added to the mixture, followed by H ₂ SO ₄ (14 mL) and the mixture was warmed to 60 ° C. After 0.5 hour, NMR revealed that the Povarov product had been completely converted to racemic compound B. The mixture was extracted with toluene (50mL). The aqueous layer was basified to pH 10 with concentrated aqueous NaOH. The basic aqueous layer was extracted with toluene (200 mL), the toluene layer was dried (Na ₂ SO ₄ ), concentrated and 7.3 g (60%) of crude 2-ethyl-6- (trifluoromethyl) -1,2,3,4-Tetrahydroquinolin-4-amine (racemic compound B) was obtained as a brown solid of 80-90% purity by NMR. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.62 (s, 1 H), 7.28 (d, 1 H), 6.45 (d, J = 8.4 Hz, 1 H), 4.03 ( s, 2H), 4.00 (s, 1H), 3.48-3.28 (m, J = 2.8 Hz, 1H), 2.27-2.08 (m, 1H) , 1.67-1.32 (m, 6H), 1.00 (t, 3H).

Example 2c) Enantiopure (2R, 4S) -2-ethyl-6- (trifluoromethyl) -1,2,3,4-tetrahydroquinolin-4-amine (Compound B) by resolution
Di-p-toluoyl-L-tartaric acid monohydrate (134.7 g, 0.33 mol, 0.75 eq) was added to a solution of crude racemic compound B (108.4 g) in methanol (1 L, 9 V), and the crystals were added. The mixture was stirred until. The resulting slush was heated to reflux, allowed to cool to room temperature, and then cooled on ice. Crystals formed which were collected by filtration and dried (99.9 g solid). This material was recrystallized from methanol (750 mL, 7V), washed with methyl tert-butyl ether (TBME) (200 mL, 2V) and 81.6 g of compound B ditoluoyltartaric acid with 99.5% enantiomeric excess (B-DTTA) salt (yield 27%) was obtained.

Example 2d) Conversion of compound B di-p-toluoyl-L-tartrate to methanesulfonate To 10 g of compound B-DTTA salt (94% enantiomeric excess), toluene (100 mL) and 2N NaOH ( 100 mL) was added. The mixture was stirred for 10 minutes, after which the layers were separated. The aqueous phase was extracted with toluene (2 × 100 mL). Next, the combined toluene layers were washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness. This gave a brown oil to which 3V of isopropanol was added. Methanesulfonic acid (MsOH) (1 mL) was added dropwise to the resulting suspension. First, the suspension became a clear mixture. After a few minutes, a solid began to form. These solids were collected, washed with TBME (2x) and dried. This gave 4 g (75% yield from compound B-TA salt) of compound BMsOH salt with an enantiomeric excess of 98.6%.

  10 V of isopropanol (IPA) (40 mL) was added and the resulting suspension was heated at reflux for 5 minutes and then allowed to cool to room temperature. A solid formed which was collected by filtration and washed with TBME. This gave 2.58 g (48% yield) of the compound BMsOH salt with an enantiomeric excess of 99.7%.

Example 2e) Conversion of compound B methanesulfonate to compound A To convert compound B methanesulfonate to compound A, a method similar to that described in WO2007 / 116922 was used.

Chemical name and formula of compound A

｛４−［（２−｛［３，５−ビス（トリフルオロメチル）ベンジル］［（２Ｒ，４Ｓ）−１―（エトキシカルボニル）−２−エチル−６−（トリフルオロメチル）−１，２，３，４−テトラヒドロキノリン−４−イル］アミノ｝ピリジン−５−イル）オキシ］ブタン酸｝

{4-[(2-} [3,5-bis (trifluoromethyl) benzyl] [(2R, 4S) -1- (ethoxycarbonyl) -2-ethyl-6- (trifluoromethyl) -1,2 , 3,4-Tetrahydroquinolin-4-yl] amino {pyridin-5-yl) oxy] butanoic acid

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Claims (18)

Formula I:

A method for preparing a racemic compound or a salt thereof,
(A) Formula II:

4-aminobenzotrifluoride according to
Formula III:

And an aldehyde according to formula IV:

Are reacted simultaneously in the presence of a solvent and optionally one or more catalysts, to give a compound of formula V:

Wherein R ₁ is H or C ₁ -C ₃ alkyl;
R ₂ is H, C ₁ -C ₃ alkyl or

It is. ), And
(B) hydrolyzing the compound of formula V to form a compound of formula (I);
Only including, prior to said step (b), separating the compound of formula (V) from the reaction mixture of step (a), the said method. The method of claim 1, wherein R ₁ is CH ₂ CH ₃ . The method of claim 1, wherein R ₁ is CH ₂ CH ₃ and R ₂ is H.   The method according to any one of claims 1 to 3, wherein the solvent used is dichloromethane, acetonitrile, ethyl acetate, toluene, or a mixture thereof.   5. The method according to claim 1, wherein the catalyst used in step a) is an acid.   The method according to claim 5, wherein the catalyst used in step a) is a Bronsted acid or a Lewis acid.   The method according to claim 5 or 6, wherein the catalyst is 4-toluenesulfonic acid. Said compound of formula V, by precipitation and / or filtration to separate from the reaction mixture of step a), said precipitation, a nonpolar solvent is carried out by adding to the reaction mixture, according to claim 1 Method. The method according to claim 8 , wherein the non-polar solvent is heptane, cyclohexane, or a mixture thereof. 10. The method according to any one of claims 1 to 9 , wherein in the step b), the compound of the formula V is hydrolyzed by heating a mixture containing the compound at 45C to 80C for 1 to 3 hours in the presence of a water-soluble acid. The method described in Crab. The method according to claim 10 , wherein the compound of formula V is hydrolyzed in the presence of a water-soluble acid and an alcohol. The method according to claim 10 or 11 , wherein the acid is hydrochloric acid. The method according to claim 11 or 12 , wherein the alcohol is ethanol. In a further step c), the formula Ia:

Wherein R ₁ is H or C ₁ -C ₃ alkyl.
According to, 2R of the racemate, separating 4S- enantiomers A method according to any one of claims 1 to 13. 15. The method of claim 14 , wherein the separation of the enantiomers according to Formula Ia is performed by resolution with a chiral resolving agent. The method according to claim 15 , wherein the chiral resolving agent is L-tartaric acid or di-p-toluoyl-L-tartaric acid. R ₁ is _CH 2 CH _3, The method according to any one of claims 14-16. A compound according to Formula Ia or a salt thereof is a compound A of the following formula:

18. The method according to any one of claims 14 to 17 , which is used for the preparation of